Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.

免疫疗法具有诱发持久反应的潜力，但目前只有少数患者有反应。免疫疗法的原发性和继发性耐药的病因是多方面的，不仅源于肿瘤内在因素，还源于癌症与其微环境之间复杂的相互作用。在解决临床免疫疗法的前沿问题时，我们描述了两类设计新药和联合疗法的方法：第一类涉及直接修饰肿瘤，而第二类则通过改变微环境间接增强免疫原性。通过系统地解决介导耐药性的因素，我们能够确定机械驱动的新方法来改善免疫疗法的疗效。